UPDATES IN REPRODUCTIVE ENDOCRINOLOGY
Hypothyroidism
Hypothyroidism is diagnosed when thyroid hormone levels are abnormally low or entirely absent. This condition can have several underlying causes, including the loss of thyroid function following a thyroidectomy. However, in most cases, hypothyroidism results from an autoimmune response targeting thyroid epitopes. When thyroid autoantibodies are present—specifically antibodies to thyroglobulin (TG Abs) and thyroid peroxidase (TPO Abs)—the condition is referred to as Hashimoto’s thyroiditis. This is the most common autoimmune disease among women of reproductive age, making it particularly significant in the field of infertility.
For anyone interested in this condition, we highly recommend a recent review article published in The Lancet (1). Even in its abstract, the article emphasizes a critical point: pregnancy—along with sex and age—requires individualized interpretation of thyroid testing results. If there is one key takeaway, it is this. This review is, without question, the most comprehensive and insightful article we have encountered on the subject in quite some time.
Reference
1. Taylor et al., Lancet 2025;404:1347-1364
The Impact of Stress on Ovarian Function
That stress can affect ovarian function has been known for quite some time. Most people, for example, are aware that travel can influence a woman’s menstrual cycle—though this effect may be related more to disruptions in circadian rhythm than to stress itself. In a recent review article, a group of Chinese investigators attempted to further clarify the association between stress and ovarian function (1). While the connection is generally accepted by most fertility specialists, quantifying stress in humans remains a significant challenge.
Moreover, if stress does negatively impact fertility, its overall effect may be limited. History has shown that children have been conceived and born even under extreme circumstances, such as during severe famines or in concentration camps during World War II. This suggests that the penetrance of stress on fertility is not absolute.
Against this backdrop, the Chinese authors offer an intriguing contribution in the International Journal of Molecular Medicine, summarizing current knowledge on the topic. They also propose potential psychological and nutritional interventions to support ovarian function. While some of their suggestions may lean toward the speculative, the paper is overall an interesting read. That said, one must be cautious not to draw premature conclusions about associations or causation. For instance, does chronic stress truly lead to primary ovarian insufficiency (POI), or is stress a consequence of POI, which may arise from other underlying causes? The article raises these questions but does not explain how one might differentiate between such possibilities in research.
Reference
1. Hu et al., Int J Molec Med 2025;55:34
Important news on testosterone effects on reproductive and behavioral phenotypes
CONFLICT STATEMENT: The Center for Human Reproduction (CHR), who also run The Reproductive Times, and several staff members are co-owners of several U.S. patents claiming fertility benefits for hypo-androgenic infertile women from supplementation with testosterone (and other androgens) and receive payment from licensing these patents.
A recent paper in Science magazine—somewhat surprisingly—linked testosterone-mediated adaptation of reproductive traits in a bird species to a single gene, which showed an unexpected pattern of expression in the brain, gonads, and—yes—even in blood! This is the second paper within weeks to offer truly revolutionary insights into hormonal effects. The other, by Loveland et al. (1), demonstrated that myostatin, a hormone produced by muscle, can control pituitary secretion of FSH, dramatically reshaping our understanding of hormonal regulation. Together, these studies revise fundamental concepts of how hormone levels are regulated and how hormone-mediated traits evolve.
The bird model used in the Science study revealed significant variation among males in terms of sexually selected behavioral and physical traits. These differences have long been attributed to testosterone. However, since testosterone is not a gene product, no single gene could be directly responsible for such variation—raising the key question: How, then, does testosterone drive these differences?
Traditionally, sex steroids derived from the gonads are believed to influence a wide range of traits, particularly behaviors that are shaped by the brain’s sensitivity to these hormones. The initial hypothesis was that differing male phenotypes might be due to variation in genes encoding androgen and estrogen receptors or in enzymes involved in testosterone synthesis. But this turned out not to be the case.
Instead, the variation was traced to the sequence and expression of the 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2) gene, which encodes an enzyme capable of inactivating testosterone. A derived form of this enzyme was found to convert testosterone to its inactive form at more than twice the rate of the original version. Even more remarkably, the study found high expression of the derived HSD17B2 gene in six behaviorally important regions of the brain. As noted in an accompanying Perspective article (2), this supports the idea that local inactivation of testosterone may explain the distinctly less “aggressive” behavior observed in certain male variants.
We especially appreciated this Perspective piece because it emphasized a growing realization in biology: our understanding has evolved from being extremely superficial to—at best—less superficial. As the author of the commentary observed, the study may point toward an emerging “rule of life” for hormone-mediated traits—or even more broadly, for all complex traits: in evolution, “every problem has many possible solutions,” and endocrine systems can be modified in almost limitless ways to generate behavioral diversity.
At CHR, we’ve long embraced this idea, referring to it as the redundancy of biological processes. We often compare it to the multiple layers of backup systems in rockets sent to the Moon—or those being planned for Mars. Perhaps even more compelling: humanity itself might not exist if evolution hadn’t built in redundancy at nearly every level of biological function. This study is just one more example, now shown in the regulation of reproductive and behavioral traits via androgens.
In short, we’re only just beginning to peel the onion.
References
1. Loveland et al., Science 20025387(67320:406-412
2. 2. Rosvall Ka. Science 2025;387(6732)”358-359
Co-secreting pituitary adenomas for growth hormone and prolactin
We’re all, of course, familiar with prolactin (PL)-secreting tumors of the pituitary—but have you heard of co-secreting adenomas that produce both human growth hormone (GH) and prolactin?
In a recent study published in the Journal of Clinical Endocrinology & Metabolism (JCEM), a team of Spanish investigators reported on 604 such cases. These adenomas have long been hypothesized to include subtypes with distinct clinical presentations and/or prognoses. With access to a large patient cohort, the researchers aimed to establish a meaningful classification.
The study included 474 individuals with pure GH excess and 130 with GH/PL co-secreting adenomas. Interestingly, the co-secreting group was diagnosed at younger ages and had lower IGF-1 levels. They also showed a higher incidence of presurgical hypopituitarism, and their tumors were more frequently macroadenomas and more invasive at the time of diagnosis (1). Unsurprisingly, permanent arginine-vasopressin deficiency was also more common in this group, although surgical cure rates were similar between the two groups.
What the paper unfortunately did not do—though we had hoped it might—was establish a clear definition for these co-secreting adenomas. Still, we can now say with certainty that they exist!
Reference
1. Wildemberg LR, Gadelha MR. J C. JCEM. 2025;110(1):e192-e193
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency throughout the lifetime
Here we have yet another endocrine condition with significant relevance to reproductive medicine—and once again, it's JCEM that brings us valuable insights. This time, the information comes in the form of a special supplement guest-edited by Richard J. Auchus, MD, PhD, one of the journal’s Associate Editors from the University of Michigan.
The supplement features eight articles that provide an excellent overview of this condition, which is caused by an inherited inability to synthesize cortisol—most often due to 21-hydroxylase deficiency. This deficiency accounts for approximately 90% to 95% of cases and is caused by mutations in the CYP21A2 gene. The classical form (as opposed to the non-classical form) occurs in about 1 in 16,000 births, whereas the non-classical form is found in roughly 1 in 200 newborns.
While we’re typically not enthusiastic about published supplements—especially those funded by the pharmaceutical industry (as this one is, by Neurocrine Biosciences, Inc.)—this is an exception. The eight articles provide a truly comprehensive, state-of-the-art update on a condition that remains widely misunderstood (1).
Reference
1. JCEM Supplement Auchus R. Guest Editor. February 2025. Supplemet 1.S1-S87